The present invention relates to substituted sulfonamide derivatives, processes for the preparation thereof, medicaments comprising these compounds and the use of substituted sulfonamide derivatives for the preparation of medicaments.
In contrast to constitutive expression of the bradykinin 2 receptor (B2R), the bradykinin 1 receptor (B1R) is not or is only weakly expressed in most tissues. Nevertheless, expression of the B1R can be induced on various cells. For example, in the course of inflammation reactions, a rapid and pronounced induction of the B1R takes place on neuronal cells, but also on various peripheral cells, such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. Thus, in the course of inflammation reactions, a switch from a B2R to a B1R dominance occurs on the cells involved. The cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) are involved considerably in this upwards regulation of B1R (Passos et al. J. Immunol. 2004, 172, 1839-1847). After activation with specific ligands, B1R-expressing cells can subsequently themselves secrete inflammation-promoting cytokines, such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J. 2000, 16, 452-458). This leads to inwards migration of further inflammation cells, e.g. neutrophilic granulocytes (Pesquero et al., PNAS 2000, 97, 8140-8145). The bradykinin B1R system can contribute towards the chronification of diseases via these mechanisms. This is demonstrated by a large number of animal studies (overviews in Leeb-Lundberg et al., Pharmacol Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem. 2006, 387, 119-126). In humans also, an increased expression of the B1R also manifests itself, e.g. on enterocytes and macrophages in the affected tissue of patients with inflammatory bowel diseases (Stadnicki et al., Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G361-366) or on T lymphocytes of patients with multiple sclerosis (Prat, 1999) or an activation of the bradykinin B2R-B1R system manifests itself in the course of infections with Staphylococcus aureus (Bengtson et al., Blood 2006, 108, 2055-2063). Infections with Staphylococcus aureus are responsible for clinical syndromes such as superficial infections of the skin up to septic shock.
Based on the pathophysiological relationships described, there is a great therapeutic potential for the use of B1R antagonists against acute and in particular chronically inflammatory diseases. These include diseases of the respiratory tract (bronchial asthma, allergies, COPD/chronic obstructive pulmonary disease, cystic fibrosis etc.), inflammatory bowel diseases (ulcerative colitis, CD/Crohn's disease etc.), neurological diseases (multiple sclerosis, neurodegeneration etc.), inflammations of the skin (atopic dermatitis, psoriasis, bacterial infections etc.) and mucosa (Behcet's disease, pelvitis, prostatitis etc.), rheumatic diseases (rheumatoid arthritis, osteoarthritis etc.), septic shock and reperfusion syndrome (following cardiac infarction, apoplexy).
The bradykinin (receptor) system is moreover also involved in the regulation of angiogenesis (potential as an angiogenesis inhibitor in cases of cancer and macula degeneration on the eye), and B1R-knockout mice are protected from induction of obesity by a particularly high-fat diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore also suitable for treatment of obesity.
B1R antagonists are particularly suitable for treatment of pain, in particular inflammatory pain and neuropathic pain (Calixto et al., Br. J. Pharmacol 2004, 1-16), and here in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143).
In the development of B1R modulators there is the problem, however, that the human and the rat B1R receptor differ so widely that many compounds which are good B1R modulators on the human receptor have only a poor or no affinity for the rat receptor. This makes animal pharmacology studies considerably more difficult, since many studies are usually conducted on the rat. However, if there is no activity on the rat receptor, neither action nor side-effect can be investigated on the rat. This has already meant that transgenic animals with human B1 receptors have been produced for animal pharmacology studies (Hess et al., Biol. Chem. 2006; 387(2):195-201). Working with transgenic animals is more expensive, needless to say, than working with the unmodified animals. However, since in the development of medicaments precisely long-term toxicity studies on the rat belong to the standard investigations, but this does not make sense in the case of a lack of activity on the receptor, the development of such compounds lacks an important established instrument for checking safety. There is therefore a need for B1R modulators, in particular those which bind both to the rat receptor and to the human receptor.